PRECLINICAL STUDY: Age‐dependent differences in sensitivity and sensitization to cannabinoids and ‘club drugs’ in male adolescent and adult rats

Abstract

Lifelong substance abuse is often initiated during adolescence; yet, most pre-clinical research in this area has been conducted in adult animals. Substantial evidence exists that the brain development that continues throughout adolescence may result in pharmacological responses that differ in a crucial manner from those of adults. The goal of this study was to evaluate age differences in motor activity following acute and repeated administration of drugs that are commonly abused by adolescents, including cocaine, Δ 9 -tetrahydrocannabinol (Δ 9 -THC), and the club drugs, ketamine and 3,4-methylenedioxymethamphetamine (MDMA). Adolescent and adult male rats were injected once daily with saline or with a dose of one of the test drugs for two 5-day dosing periods, separated by a 2-day drug holiday during which they remained in their home cages. Following each injection, rats were placed in a locomotor chamber for a 20-minute session. The potencies of cocaine, ketamine and MDMA for producing motor stimulation were less in male adolescents than in male adults. Furthermore, sensitization to the club drug, ketamine, developed after repeated dosing in adults, but not adolescents. In contrast, adolescents were initially more sensitive to the stimulatory effects of low doses of Δ 9 -THC than were adults, although rapid tolerance occurred. These results suggest that adolescents are less sensitive to the acute and repeated stimulant effects of some, but not all, of the drugs that are preferentially abused by this age group. This differential sensitivity may contribute to the different patterns of use that have been noted in adolescent versus adult drug abusers.

Neurotoxic Effects of MDMA (Ecstasy) on the Developing Rodent Brain

“…These findings are in line with data showing an age-dependent susceptibility, with a higher sensitivity of 5-HT neurons to MDMA-induced toxicity and an increased lethality in adult rats compared to adolescent rats [Broening et al, 1994;Wiley et al, 2008]. Altogether, there seems to be a biphasic vulnerability to MDMA-induced apoptotic cell death in the developing rat brain.…”

Previous Exposure to Δ9-Tetrahydrocannibinol Enhances Locomotor Responding to but Not Self-Administration of Amphetamine

“…Some studies have reported that exposure to these compounds fails to enhance their behavioral effects (Arnold et al, 1998;Varvel et al, 2007;Wiley et al, 2008), although others have demonstrated sensitization (Cadoni et al, 2001(Cadoni et al, , 2008Rubino et al, 2001). Differences in the doses and compounds administered during exposure may account for some of the different findings reported.…”

Differences between adolescents and adults in the acute effects of PCP and ketamine and in sensitization following intermittent administration

“…Since previous work demonstrated reduced locomotor stimulation in adolescents to psychostimulants such as cocaine (Laviola et al, 1995; Izenwasser and French, 2002; Wiley et al, 2008; Zombeck et al, 2009) and methamphetamine (Zombeck et al, 2009), it was hypothesized that periadolescent animals would exhibit reduced stimulant effects to PCP or ketamine when compared to adults. Surprisingly, young periadolescent animals (PND 30) exhibited a greater stimulant response to an acute administration of either PCP or ketamine when compared to older adolescents (PND 38) or adults (PND 60).…”

“…Specifically, adolescents show reduced locomotor stimulation and less sensitization than adults to psychostimulants such as cocaine (Laviola et al, 1995; Izenwasser and French, 2002; Wiley et al, 2008; Zombeck et al, 2009) and methamphetamine (Zombeck et al, 2009). Age differences in the development of sensitization to dissociatives have not been well studied and are therefore less understood.…”